Abstract
BackgroundWe have previously shown that the expression of CBX7 is drastically decreased in several human carcinomas and that its expression progressively decreases with the appearance of a highly malignant phenotype. The aim of our study has been to investigate the mechanism by which the loss of CBX7 expression may contribute to the emergence of a more malignant phenotype.MethodsWe analyzed the gene expression profile of a thyroid carcinoma cell line after the restoration of CBX7 and, then, analyzed the transcriptional regulation of identified genes. Finally, we evaluated the expression of CBX7 and regulated genes in a panel of thyroid and lung carcinomas.ResultsWe found that CBX7 negatively or positively regulates the expression of several genes (such as SPP1, SPINK1, STEAP1, and FOS, FOSB, EGR1, respectively) associated to cancer progression, by interacting with their promoter regions and modulating their transcriptional activity. Quantitative RT-PCR analyses in human thyroid and lung carcinoma tissues revealed a negative correlation between CBX7 and its down-regulated genes, while a positive correlation was observed with up-regulated genes.ConclusionIn conclusion, the loss of CBX7 expression might play a critical role in advanced stages of carcinogenesis by deregulating the expression of specific effector genes.
Highlights
chromobox homolog 7 (CBX7) is a Polycomb protein member of the polycomb repressive complex 1 (PRC1), a multiprotein complex that together with the polycomb repressive complex 2 (PRC2), maintains important developmental genes in a transcriptionally repressed state [1,2,3]
To investigate the mechanism by which the loss of CBX7 expression may contribute to the acquisition of a malignant phenotype, we analysed the gene expression profile of a thyroid carcinoma cell line (FRO) in which the expression of CBX7 was restored (FRO-CBX7, Figure 1A)
Among the genes regulated by CBX7 in human thyroid carcinoma cells we concentrated our attention on FBJ murine osteosarcoma viral oncogene homolog (FOS), FBJ murine osteosarcoma viral oncogene homolog B (FOSB) and early growth response 1 (EGR1) (Table 1) that were positively regulated, and SPP1, SPINK1 and STEAP1 (Table 2) that were, negatively regulated by CBX7, since these genes are known to play a relevant role in the acquisition of a fully malignant phenotype
Summary
CBX7 is a Polycomb protein member of the polycomb repressive complex 1 (PRC1), a multiprotein complex that together with the polycomb repressive complex 2 (PRC2), maintains important developmental genes in a transcriptionally repressed state [1,2,3]. We have previously demonstrated that the CBX7 gene is drastically down-regulated in thyroid carcinomas and its expression progressively decreases with malignant grade and neoplastic stage [4]. It has been recently demonstrated that CBX7 is able to positively regulate the expression of the gene encoding the Ecadherin [11] that is known to play a critical role in maintaining normal epithelial cell morphology, and whose loss of expression represents a general feature of the epithelial-mesenchymal transition [12,13]. A direct correlation between the levels of E-cadherin and CBX7 expression has been reported in thyroid and pancreatic carcinomas [7,11] These results would suggest that the loss of the CBX7 gene expression may play a critical role in the late stages of human carcinoma progression. The aim of our study has been to investigate the mechanism by which the loss of CBX7 expression may contribute to the emergence of a more malignant phenotype
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